PuSH - Publikationsserver des Helmholtz Zentrums München

Ghodousi, A.* ; Iannucci, I.* ; Saluzzo, F.* ; Dreisbach, J.* ; Mirold-Mei, S.* ; Hoelscher, M. ; Cirillo, D.M.*

Low-level BTZ-043 resistance in Mycobacterium tuberculosis and cross-resistance to bedaquiline and clofazimine.

IJTLD Open 2, 604 - 609 (2025)
Verlagsversion Forschungsdaten DOI PMC
Creative Commons Lizenzvertrag
BACKGROUND: Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis complex (MTBC) remain a significant global health challenge. This study investigates resistance mechanisms to BTZ-043, a novel decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) inhibitor, and its potential cross-resistance with bedaquiline (BDQ) and clofazimine (CFZ). METHODS: BTZ-043-resistant mutants were generated in M. tuberculosis H37Rv by serial exposure to escalating drug concentrations. Minimum inhibitory concentrations (MICs) for BTZ-043 were determined for 130 wild-type strains, including 60 H37Rv independent cultures and 70 diverse clinical isolates, plus 33 non-wild-type clinical strains with known BDQ susceptibility. MICs were correlated with whole-genome sequencing (WGS) data to identify genetic factors underlying resistance. RESULTS: The MIC distribution for clinical MTBC strains was similar to the reference strain, with a mode of 0.002 μg/mL. WGS of resistant mutants revealed mutations in dprE1 and Rv0678. Rv0678 and dprE1 mutations resulted in 4- to 8-fold and >1,000-fold increase in MIC compared with the reference mode, respectively. Sequential clinical strains from BDQ-treated patients showed increased MICs and Rv0678 mutations, indicating low-level cross-resistance. However, Rv0678 mutations in BDQ-susceptible strains did not affect BTZ-043 MICs. CONCLUSION: Rv0678 mutations confer low-level cross-resistance to BTZ-043, BDQ, and CFZ, with variable effects on susceptibility. These findings highlight the complexity of resistance mechanisms and the need for ongoing surveillance and early resistance assessments in drug development.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Bedaquiline ; Clofazimine
ISSN (print) / ISBN 3005-7590
e-ISSN 3005-7590
Zeitschrift IJTLD Open
Quellenangaben Band: 2, Heft: 10, Seiten: 604 - 609 Artikelnummer: , Supplement: ,
Verlag International Union Against Tuberculosis and Lung Disease
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Global Health (UGH)